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Shahid Husain, Anis Ahmad, sudha Singh; Novel Targets of Delta Opioid-Receptor for RGC Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2481.
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© ARVO (1962-2015); The Authors (2016-present)
This study was designed to identify the downstream targets of delta opioid-receptors for RGC neuroprotection during glaucomatous injury.
Brown Norway rats were used to elevate intraocular pressure (IOP) by injecting 50 µL of 2M hypertonic saline into the circumferential limbal veins. IOP was recorded as the average of 6-8 consecutive measurements prior to surgery (baseline IOP) and weekly after treatment, using a calibrated Tonolab tonometer. Animals were either treated with delta opioid-receptor agonist, SNC-121 (1 mg/kg; i.p) or Br-cAMP (1 mg/kg; i.p), daily for 7 days. Pattern electroretinograms (PERG), retinal ganglion cells (RGCs) in flat mount, and axons were counted 4-6 week post injury. The changes in the expression patterns of PI3K/Akt and phospho-cyclic AMP-response element binding protein (p-CREB) were determined by Western blotting and immunohistochemistry.
Glaucomatous injury caused significant (p<0.05) reduction in pattern ERG (PERG), axonal, and RGC numbers at 6th week, post glaucomatous injury. PERG deficits, axonal, and RGC survival were significantly improved by SNC-121 treatment. A sustained (7-42 days, post injury) decline in PI3K/Akt and CREB phosphorylation is seen in the glaucomatous retina and optic nerve, which was reversed by SNC-121 treatment. Classically, opioid-receptors are linked to pertussis toxin sensitive Gi proteins which inhibit adenylyl cyclase activity and attenuate cAMP formation. However, our data prompted us to believe that either δ-opioid receptors are linked to Gs proteins or opioid-receptor-activation leads to AC superactivation for cAMP production. Thus we measured the levels of cAMP at day 42 post glaucomatous injury in untreated and SNC-121 treated rats. The level of cAMP was decreased by 29% in glaucomatous retinas. Surprisingly, we have seen an increase in the production of cAMP in SNC-121-treated normal and glaucomatous eyes. Additionally, we found that Br-cAMP increases axonal transport, RGC neuroprotection, and CREB phosphorylation.
These data provide evidence that PI3K/Akt and CREB, a transcription factor, are the potential neuroprotective downstream targets of δ-opioid-receptors for RGC neuroprotection. Data also provide novel information about the linkage of δ-opioid-receptors with Gs-proteins and/or AC superactivation, which will open new avenues for RGC neuroprotection.
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